Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
James Franck Institute, The University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2024 Feb 15;15(1):1408. doi: 10.1038/s41467-024-45514-6.
The Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) is a membrane protein containing a voltage-sensing domain (VSD) that is homologous to VSDs from voltage-gated ion channels responsible for cellular excitability. Previously published crystal structures of Ci-VSD in putative resting and active conformations suggested a helical-screw voltage sensing mechanism in which the S4 helix translocates and rotates to enable exchange of salt-bridge partners, but the microscopic details of the transition between the resting and active conformations remained unknown. Here, by combining extensive molecular dynamics simulations with a recently developed computational framework based on dynamical operators, we elucidate the microscopic mechanism of the resting-active transition at physiological membrane potential. Sparse regression reveals a small set of coordinates that distinguish intermediates that are hidden from electrophysiological measurements. The intermediates arise from a noncanonical helical-screw mechanism in which translocation, rotation, and side-chain movement of the S4 helix are only loosely coupled. These results provide insights into existing experimental and computational findings on voltage sensing and suggest ways of further probing its mechanism.
秀丽隐杆线虫电压感应磷酸酶（Ci-VSP）是一种膜蛋白，包含一个与负责细胞兴奋性的电压门控离子通道的 VSD 同源的电压感应结构域（VSD）。先前发表的 Ci-VSD 在假定的静息和激活构象中的晶体结构表明，存在一种螺旋式螺杆电压感应机制，其中 S4 螺旋体迁移并旋转，以实现盐桥配体的交换，但静息和激活构象之间的转变的微观细节仍然未知。在这里，我们通过将广泛的分子动力学模拟与最近基于动态算子开发的计算框架相结合，阐明了在生理膜电位下静息-激活转变的微观机制。稀疏回归揭示了一组可区分隐藏在电生理学测量之外的中间体的坐标。这些中间体源自一种非典型的螺旋式螺杆机制，其中 S4 螺旋体的迁移、旋转和侧链运动仅松散耦合。这些结果为现有关于电压感应的实验和计算结果提供了深入的了解，并提出了进一步探测其机制的方法。
